Cited by 281Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorTryptophan and brain disorders

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Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response.

Andrews, Paul W., Bharwani, Aadil, Lee, Kyuwon R., Fox, Molly, Thomson, J. Anderson·2015·Neuroscience & Biobehavioral Reviews

DOI 10.1016/j.neubiorev.2015.01.018

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Abstract

The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.

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Authors: Andrews, P. W., Bharwani, A., Lee, K. R., Fox, M., & Thomson, J. A.
Affiliations: McMaster University (CA)
University of California, Irvine (US)
University of Virginia (US)
Corresponding author: Andrews, Paul W.
ORCID: Andrews, Paul W.
Bharwani, Aadil
Lee, Kyuwon R.
Fox, Molly
Venue: Neuroscience & Biobehavioral Reviews
Publisher: Elsevier BV
Published: 2015-04
Volume: 51
Pages: 164-188
ISSN: 0149-7634 (ISSN-L)
DOI: 10.1016/j.neubiorev.2015.01.018
OpenAlex: W2163250198
Cited by: 281
References: 459
Citations by year: 2026: 12 · 2025: 13 · 2024: 25 · 2023: 21 · 2022: 20 · 2021: 34 · 2020: 31 · 2019: 36 · 2018: 37 · 2017: 24 · 2016: 17 · 2015: 10
FWCI: 3.69
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuroscience & Biobehavioral Reviews (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords: serotonin, depression, antidepressant response, selective serotonin reuptake inhibitors, melancholia, energy homeostasis, treatment delay, animal models of depression
MeSH terms: Animals, Antidepressive Agents, Brain, Depressive Disorder, Humans, Serotonin, Selective Serotonin Reuptake Inhibitors

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Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response.

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